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Arginase Inhibition Protects against Allergen-induced Airway Obstruction, Hyperresponsiveness, and Inflammation

¹ Department of Molecular Pharmacology, University Center for Pharmacy, University of Groningen, Groningen, The Netherlands; ² NV Organon, Oss, The Netherlands; and ³ Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes, Paris, France

Correspondence and requests for reprints should be addressed to Harm Maarsingh, Ph.D., Department of Molecular Pharmacology, University Center for Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. E-mail: h.maarsingh{at}rug.nl

Rationale: In a guinea pig model of allergic asthma, using perfused tracheal preparations ex vivo, we demonstrated that L-arginine limitation due to increased arginase activity underlies a deficiency of bronchodilating nitric oxide (NO) and airway hyperresponsiveness (AHR) after the allergen-induced early and late asthmatic reaction.

Objectives: Using the same animal model, we investigated the acute effects of the specific arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) and of L-arginine on AHR after the early and late reaction in vivo. In addition, we investigated the protection of allergen-induced asthmatic reactions, AHR, and airway inflammation by pretreatment with the drug.

Methods: Airway responsiveness to inhaled histamine was measured in permanently instrumented, freely moving guinea pigs sensitized to ovalbumin at 24 hours before allergen challenge and after the allergen-induced early and late asthmatic reactions by assessing histamine PC₁₀₀ (provocative concentration causing a 100% increase of pleural pressure) values.

Measurements and Main Results: Inhaled ABH acutely reversed AHR to histamine after the early reaction from 4.77 ± 0.56-fold to 2.04 ± 0.34-fold (P < 0.001), and a tendency to inhibition was observed after the late reaction (from 1.95 ± 0.56-fold to 1.56 ± 0.47-fold, P < 0.10). Quantitatively similar results were obtained with inhaled L-arginine. Remarkably, after pretreatment with ABH a 33-fold higher dose of allergen was needed to induce airway obstruction (P < 0.01). Consequently, ABH inhalation 0.5 hour before and 8 hours after allergen challenge protected against the allergen-induced early and late asthmatic reactions, AHR and inflammatory cell infiltration.

Conclusions: Inhalation of ABH or L-arginine acutely reverses allergen-induced AHR after the early and late asthmatic reaction, presumably by attenuating arginase-induced substrate deficiency to NO synthase in the airways. Moreover, ABH considerably reduces the airway sensitivity to inhaled allergen and protects against allergen-induced bronchial obstructive reactions, AHR, and airway inflammation. This is the first in vivo study indicating that arginase inhibitors may have therapeutic potential in allergic asthma.

Key Words: allergic asthma • 2(S)-amino-6-boronohexanoic acid • L-arginine • nitric oxide • guinea pigs

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Airway arginase expression and activity are increased in allergic asthma, contributing to airway hyperresponsiveness (AHR). However, the effectiveness of inhaled arginase inhibitors to reduce and/or prevent allergen-induced AHR has not been studied yet. What This Study Adds to the Field Inhalation of an arginase inhibitor reduced airway sensitivity to inhaled allergen and protected against early and late asthmatic reactions, including AHR and airway inflammation.